Investigators have long been interested in improving response rates in metastic breast cancer by attempting to increase proliferative activity (PA) and then applying cell cycle specific chemotherapy at the presumed height of stimulation. In vitro studies have shown that an increase in PA results from exposure to .5-1 nM 17-B estradiol(E2) alhough greater than 10 nM may be inhibitory. Clinical trials in which patients have been pretreated with oral estrogens before receiving chemotherapy have had mixed results. However all these trials have (1) used antiestrogens immediately preceeding the estrogen which may have prevented stimulation, (2) have not measured serum levels of E2 or antiestrogens and (3) have not obtained serial tumor samples to document if or when treatment was actually producing an increase in the number of cells in cycle. In a preliminary study utilizing once daily oral estradiol and serial biopsies, we found an increase in S phase in 2/4 patients. However, time to increase in S phase was variable and continuous 1 nM E2 levels were not maintained. We did find that micronized E2 vaginal suppositories reliably produced .5-1 nM E2 levels without large biologically important increases in estrone (E1). Peak E2 levels were present within 1 hour of suppository insertion and E2 and FSH levels approached baseline within 48 hours of discontinuation following chronic (72-96 hour) adminisration. Further studies are needed to address the following quastions. 1) What proportion of patients will exhibit a significant increase in cells in cycle if exposed to continuouus 1 bN levels of E2 which closely mimic tissue culture conditions? 2) When can an increase in PA be expected to occur relative to initiation of E2. We will address these questions by obtaining serial samples of tumor from patients with locally advanced disease as well as from patients with soft tissue metastases and malignant pleural effusions before and during the initial 72 hours of intravaginal E2 administration. During and after the intravaginal E2 we will also monitor E2, estrone (E1) and FSH levels. At the conclusion of this study we will know if and when E2 can induce an increase in PA in a significant number of patients. This information will then be used to design a randomized trial questionning the raltive merit of hormone synchronization for the treatment of breast cancer.